Project Summary/Abstract PTI-125 is a novel small molecule Alzheimer's disease (AD) therapeutic candidate with a novel target and mechanism of action. PTI-125 binds and reverses an altered conformation of the scaffolding protein filamin A (FLNA) to prevent A?42's tight binding to and toxic signaling via the ?7-nicotinic acetylcholine receptor (?7nAChR) as well as A?42's aberrant activation of toll-like receptor 4 (TLR4). Hence, by restoring FLNA's native shape and blocking these two toxic cascades, PTI-125 reduces both tau hyperphosphorylation and neuroinflammation. Downstream effects include reduced neurofibrillary lesions and amyloid deposits, suggesting disease modification, and improved synaptic plasticity and function of ?7nAChR, NMDAR and insulin receptors, suggesting symptomatic improvement. We will pursue a label claim of symptomatic improvement instead of the more difficult claim of disease modification and will therefore conduct clinical studies in mild-to-moderate AD. Under a US IND, the first-in-human clinical trial showed no drug- related adverse effects (AEs) and dose proportional pharmacokinetics (PK). Two Phase 2 multidose studies in mild-to-moderate AD patients of 1-month and 3-month duration, respectively, will measure CSF and plasma/lymphocyte biomarkers and psychiatric/behavioral measures. The already underway 1-month study, a 12-patient open-label study, will also assess PK of twice daily oral dosing of the tablet formulation. The upcoming 3-month blinded study will additionally assess cognition, but not PK. Excellent safety margins have been demonstrated in a 3-month toxicity study in dog and in a 6-month toxicity study in rat. The completion of the 9-month dog toxicity study in May 2019, along with the 6-month rat study, will support clinical trials of any duration. We therefore propose to add a 1-year open-label extension to the 3-month clinical trial both to encourage enrollment and to start our safety database required by FDA. This proposal also includes scale-up and manufacture of PTI-125 tablets to supply this clinical trial, as well as analytical method improvement for PTI-125 Drug Substance to Phase 2/3 standards. The faster acquisition of endpoints for the 3-month blinded clinical trial, along with longer-term dosing for safety and monitoring of disease progression, should greatly enhance interest by potential pharma partners.